title: MeCP2: a novel Huntingtin interactor.
abstract: Transcriptional dysregulation has been proposed to play a major role in the pathology of Huntington's disease (HD). However, the mechanisms that cause selective downregulation of target genes remain unknown. Previous studies have shown that mutant huntingtin (Htt) protein interacts with a number of transcription factors thereby altering transcription. Here we report that Htt directly interacts with methyl-CpG binding protein 2 (MeCP2) in mouse and cellular models of HD using complimentary biochemical and Fluorescent Lifetime Imaging to measure Förster Resonance Energy Transfer approaches. Htt-MeCP2 interactions are enhanced in the presence of the expanded polyglutamine (polyQ) tract and are stronger in the nucleus compared with the cytoplasm. Furthermore, we find increased binding of MeCP2 to the promoter of brain-derived neurotrophic factor (BDNF), a gene that is downregulated in HD, in the presence of mutant Htt. Finally, decreasing MeCP2 levels in mutant Htt-expressing cells using siRNA increases BDNF levels, suggesting that MeCP2 downregulates BDNF expression in HD. Taken together, these findings suggest that aberrant interactions between Htt and MeCP2 contribute to transcriptional dysregulation in HD.
authors.affiliation: Department of Neurology and The McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Karen N
authors.initials: KN
authors.lastname: McFarland
authors.forename: Megan N
authors.initials: MN
authors.lastname: Huizenga
authors.forename: Shayna B
authors.initials: SB
authors.lastname: Darnell
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Sangrey
authors.forename: Oksana
authors.initials: O
authors.lastname: Berezovska
authors.forename: Jang-Ho J
authors.initials: JH
authors.lastname: Cha
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D014158:Transcription, Genetic
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins